Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2

Christopher Duncan (1) , Benjamin Thompson (1) , Rui Chen (1) , Gillian Rice (2) , Florian Gothe (1, 3) , Dan Young (4) , Simon Lovell (2) , Victoria Shuttleworth (1) , Vicky Brocklebank (1) , Bronte Corner (1) , Andrew Skelton (1) , Vincent Bondet (5) , Jonathan Coxhead (1) , Darragh Duffy (5) , Cécile Fourrage (6) , John Livingston (7) , Julija Pavaine (8, 2) , Edmund Cheesman (8) , Stephania Bitetti (8) , Angela Grainger (1) , Meghan Acres (1) , Barbara Innes (1) , Aneta Mikulasova (1) , Ruyue Sun (1) , Rafiqul Hussain (5) , Ronnie Wright (2, 8) , Robert Wynn (9) , Mohammed Zarhrate (10) , Leo Zeef (2) , Katrina Wood (11) , Stephen Hughes (9, 8) , Claire Harris (1) , Karin Engelhardt (1) , Yanick Crow (10, 12, 13) , Richard Randall (4) , David Kavanagh (1, 11) , Sophie Hambleton (1, 11) , Tracy Briggs (2, 8)

1 Newcastle University [Newcastle]
2 University of Manchester [Manchester]
3 LMU - Ludwig-Maximilians-Universität München
4 University of St Andrews [Scotland]
5 Immunobiologie des Cellules dendritiques
6 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
7 University of Leeds
8 Central Manchester University Hospitals NHS Foundation Trust
9 Royal Manchester Children's Hospital
10 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
11 Newcastle Upon Tyne Hospitals NHS Foundation Trust
12 UPD5 - Université Paris Descartes - Paris 5
13 University of Edinburgh

Excessive type I interferon (IFNα/β) activity is implicated in a spectrum of human disease, yet its direct role remains to be conclusively proven. We investigated two siblings with severe early-onset autoinflammatory disease and an elevated IFN signature. Whole-exome sequencing revealed a shared homozygous missense Arg148Trp variant in STAT2, a transcription factor that functions exclusively downstream of innate IFNs. Cells bearing STAT2R148W in homozygosity (but not heterozygosity) were hypersensitive to IFNα/β, which manifest as prolonged Janus kinase-signal transducers and activators of transcription (STAT) signaling and transcriptional activation. We show that this gain of IFN activity results from the failure of mutant STAT2R148W to interact with ubiquitin-specific protease 18, a key STAT2-dependent negative regulator of IFNα/β signaling. These observations reveal an essential in vivo function of STAT2 in the regulation of human IFNα/β signaling, providing concrete evidence of the serious pathological consequences of unrestrained IFNα/β activity and supporting efforts to target this pathway therapeutically in IFN-associated disease.

Domains: Life Sciences [q-bio]; Immunology

Christopher Duncan, Benjamin Thompson, Rui Chen, Gillian Rice, Florian Gothe, et al.. Severe type I interferonopathy and unrestrained interferon signaling due to a homozygous germline mutation in STAT2. Science Immunology, 2019, 4 (42), pp.eaav7501. ⟨10.1126/sciimmunol.aav7501⟩. ⟨pasteur-02430168⟩